This application seeks continued support for this Program because progress made during the first cycle indcates that the 3 central hypotheses are correct: 1) Defective/deficient immune complex (1C) clearance proteins are risk factors for SLE nephritis; 2) The magnitude of chemokine expression in response to 1C in the kidney predicts severe nephritis and its persistence; 3) SLE flare may result from a clinical trigger interacting with a genetic predisposition. In the next Program cycle, the OVERALL OBJECTIVE will be to develop models that predict SLE status, based on the central hypotheses of the first cycle. If SLE activation, flare severity, and flare prognosis can be predicted, it can likely be controlled by existing therapies more effectively and with less toxicity. The Program's hypothesis testing will continue through the two Study Arms. ARM 1 (SLE Family Genetic Testing) is a crosssectional study of SLE patients and family members (target goal 400 families, 50% with renal lupus) and matched normals (target goal 450). Analysis Plan: Use the ARM 1 genetic and clinical database (comprised of 136 items/individual) to identify genes that predispose to SLE, or modify the phenotype of SLE, and identify interactions between candidate SLE genes. ARM 2 (the Ohio SLE Study, OSS) is a meticulous, longitudinal study of recurrently active SLE (106 patients to date, 67% renal, median follow-up 33 months) with protocol testing and data collection daily, monthly, and bimonthly. Analysis plan: Use the ARM 2 database (>90,000 items) and specimen bank (>20,000 items, including RBC, WBC, RNA, plasma, and urine), obtained from >150 SLE flares to identify SLE biomarkers based on 1C clearance proteins in SLE (Projects 1,2,4, Core B, C), pathways that regulate inflammation in SLE (Projects 3,4, Core B, C), and clinical variables involved in the pathogenesis of lupus flare (Projects 1- 4, Core A,B, C). Additionally, pilot intervention trials to suppress SLE nephritis activity (n=2, embedded in Project 4) will be undertaken in this cycle, based on observational studies of our unique clinical database. Conclusions: This Program will identify genetic, clinical, and environmental factors that predispose to and regulate SLE nephritis flare, with the goal of improving therapeutic efficacy and reducing treatment morbidity. Lay Summary: This research will lead to earlier diagnosis and treatment of kidney flares in lupus, and more effective use of available medications, resulting in improved clinical outcomes for SLE patients.